Faculty Collaboration Database

Diapocynin and apocynin administration fails to significantly extend survival in G93A SOD1 ALS mice. Neurobiol Dis 2012 Jan;45(1):137-44

Date

08/09/2011

Pubmed ID

21820513

Pubmed Central ID

PMC3710723

DOI

10.1016/j.nbd.2011.07.015

Scopus ID

2-s2.0-81955168003 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

NADPH oxidase has recently been identified as a promising new therapeutic target in ALS. Genetic deletion of NADPH oxidase (Nox2) in the transgenic SOD1(G93A) mutant mouse model of ALS was reported to increase survival remarkably by 97 days. Furthermore, apocynin, a widely used inhibitor of NADPH oxidase, was observed to dramatically extend the survival of the SOD1(G93A) ALS mice even longer to 113 days (Harraz et al. J Clin Invest 118: 474, 2008). Diapocynin, the covalent dimer of apocynin, has been reported to be a more potent inhibitor of NADPH oxidase. We compared the protection of diapocynin to apocynin in primary cultures of SOD1(G93A)-expressing motor neurons against nitric oxide-mediated death. Diapocynin, 10 μM, provided significantly greater protection compared to apocynin, 200 μM, at the lowest statistically significant concentrations. However, administration of diapocynin starting at 21 days of age in the SOD1(G93A)-ALS mouse model did not extend lifespan. Repeated parallel experiments with apocynin failed to yield protection greater than a 5-day life extension in multiple trials conducted at two separate institutions. The maximum protection observed was an 8-day extension in survival when diapocynin was administered at 100 days of age at disease onset. HPLC with selective ion monitoring by mass spectrometry revealed that both apocynin and diapocynin accumulated in the brain and spinal cord tissue to low micromolar concentrations. Diapocynin was also detected in the CNS of apocynin-treated mice. The failure to achieve significant protection with either apocynin or diapocynin raises questions about the utility for treating ALS patients.

Author List

Trumbull KA, McAllister D, Gandelman MM, Fung WY, Lew T, Brennan L, Lopez N, Morré J, Kalyanaraman B, Beckman JS

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetophenones
Amyotrophic Lateral Sclerosis
Animals
Biphenyl Compounds
Longevity
Mice
Mice, Neurologic Mutants
Motor Neurons
Rats
Rats, Transgenic
Superoxide Dismutase
Treatment Outcome